AMG-3969 is an effective glucokinase-glucokinase regulatory protein interaction (GK-GKRP) disruptor (IC50: 4 nM).

GK-GKRP:4 nM (cell free)

AMG-3969在细胞活性方面表现出强效(细胞外半数有效浓度EC50为0.202 μM；半数抑制浓度IC50为4 nM)[1,2]。在体外（分离的肝细胞中），AMG-3969有效地逆转了GKRP对GK活性的抑制作用，并促进GK的转位[3]。

AMG-3969 (100 mg/kg) 在血糖降低方面显示显著效果，特别是在8小时时点观察到强大的疗效（降低56%）[1]。在多种糖尿病啮齿动物模型中，AMG-3969能够将血糖水平正常化。AMG-3969在大鼠体内具有良好的药代动力学（PK）属性（75%），并在db/db小鼠中以剂量依赖的方式显著降低血糖水平[2]。AMG-3969在三种糖尿病模型中展现出剂量依赖的疗效，包括饮食诱导的肥胖（DIO）、ob/ob和db/db小鼠；然而，AMG-3969对于正常血糖的C57BL/6（B6）小鼠降血糖无效。AMG-3969在促进碳水化合物基质方面高度有效。通过观察到的呼吸交换比率增加，AMG-3969在单剂量后的次夜及次日引发碳水化合物氧化的持续变化[3]。

Diabetic db/db mice are used in the study. At 8:00 AM, mice are bled via retro-orbital sinus puncture and blood glucose values are determined and used to randomize the animals in which their averages are similar, and only mice with blood glucose ranges between 300 and 500 mg/dL are included. Vehicle (2% hydroxypropyl methylcellulose, 1% Tween 80, pH 2.2 adjusted with MSA) or AMG-3969 (10, 30, 100 mg/kg) are gavaged at 9:00 AM. Blood glucose is measured at 4, 6, or 8 h posttreatment. At each time point, a 15 μL sample of whole blood is analyzed for drug exposure [1].